13:40 - 15:10
Room: ANA Crowne Plaza “Ohtori” Room C
Workshop Session
Koji Yasutomo, Warren Leonard
Mutation of arginine 285 in IRF3 to glutamine selectively impairs activation of IRF3 by STING and TRIF dependent pathways.
Line Lykke Andersen1, Louise Kragh Dalskov1, Hans Henrik Gad1, Trine Hyrup Mogensen2, Rune Hartmann1
1Department of Molecular Biology and Genetics, Aarhus University, Aarhus. Denmark., Aarhus, Denmark, 2Department of Infectious Diseases, Aarhus University Hospital,, Aarhus, Denmark

The detection of viral infections is initiated by pattern recognition receptors (PRRs) that signal through the downstream adaptors MAVS, TRIF and STING to activate interferon regulatory factor 3 (IRF3). IRF3 is a positive regulator of both type I and type III interferons (IFNs) as well as a series of antiviral genes. IRF3 is activated when a positively charged surface on IRF3 is bound by a phosphorylated adaptor. Several recent studies have focused on the functional significance of the positively charged surface on IRF3, which is also the focus of this project. We originally identified the R285Q mutation in a patient suffering from herpes simplex encephalitis (HSE) who exhibited a markedly reduced response to infection with herpes virus but not to the RNA viruses we tested (Andersen, LL, et al., J Exp Med, 2015). As this observation is contradictory to the standard perception of IRF3 function, we decided to investigate the mechanism by which IRF3 is activated by the different adaptor proteins in more details. Basic surface residues within the region of IRF3 involved in docking to the adaptors were mutated and the effect of these mutations on the activation of IRF3 by each of the three adaptors was measured. The R211Q mutation led to an almost complete loss of IRF3 activity regardless of which pathway was used to activate IRF3. In contrast, the R285Q mutation resulted in a strong loss of activity when activated through both TRIF and STING but much less so when activated through MAVS. These observation are in agreement in what we found in the patient and suggest differences in how the three adaptors, MAVS, TRIF and STING, activate IRF3.

Workshop 5, “Genetic disorders in cytokines and inflammation”
Rune Hartmann
Presentation type:
Oral Presentation
ANA Crowne Plaza “Ohtori” Room C
Koji Yasutomo, Warren Leonard
Monday, 30 October 2017
14:00 - 14:10
Session times:
13:40 - 15:10